Radical Cascade Research Articles

Organic Photoredox Catalytic Difluoroalkylation of Unactivated Olefins to Access Difluoro-Containing Tetrahydropyridazines.

Herein, we disclose a readily available phenothiazine derivative as an organocatalyst, which upon excitation with 371 nm light acquires a strongly reducing power and serves to induce the radical cascade difluoromethylation/cyclization reaction of N-homoallylacetohydrazides. A variety of CF2COR-tetrahydropyridazines have been obtained in moderate to excellent yields. This catalytic platform proceeds under metal-free conditions with a wide substrate scope and broad functional group compatibility, which unlocks the new reactivity of phenothiazine derivatives and adds significant synthetic value to N-heterocycles.

Photocatalytic Silylation of Aryl Alkynoates: Synthesis of Silylated Coumarins

AbstractHerein, we report the photocatalytic synthesis of 3‐silyl coumarins using hydrosilanes as the silyl radical source with aryl alkynoates. Readily prepared N‐aminopyridinium salts act as hydrogen atom transfer reagents for generating silyl radicals under photoredox catalysis. The reaction proceeds through a silyl radical addition to alkyne followed by radical cascade cyclization/migration with subsequent oxidation and aromatization to give the desired 3‐silyl coumarins in 34–89% yield.

Manganese- Mediated Cascade Radical Oxidative Cyclization/1,6-Conjugate Addition of Unsaturated Oximes with p-Quinone methides: Facile Access to β,β-Diarylmethine Isoxazolines.

A simple and efficient strategy for the synthesis of structurally diverse β,β-diarylmethine substituted isoxazoline derivatives have been developed. This approach employs a manganese-promoted oxidative cyclization coupled with a 1,6-conjugate addition of unsaturated oximes to p-quinone methides. The key features of this study include the formation of C-O and C-C bonds through intramolecular and intermolecular interactions, facilitated by in situ generated iminoxyl radicals. β,β-diarylmethine substituted isoxazolines, bearing a wide range of functional groups, were isolated in high yields.

Synthesis of Naphthalenones Via Photo‐Induced Radical Cascade Fluoroalkylation/Cyclization of Alkenes

AbstractHerein, we report a photoredox‐catalyzed fluoroalkylation of activated alkenes via fluorinated alkyl‐centered radical induced radical addition/annulation/SET/deprotonation in a domino fashion using 4CzIPN as photocatalyst. The protocol features room temperature, transition metal free, high yields and simple operation, affording a facile and efficient strategy to access fluorine‐containing naphthalenone.

A nucleobase-driven P450 peroxidase system enables regio- and stereo-specific formation of C─C and C─N bonds

P450 peroxidase activities are valued for their ability to catalyze complex chemical transformations using economical H2O2; however, they have been largely underexplored compared to their monooxygenase and peroxygenase activities. In this study, we identified an unconventional P450 enzyme, PtmB, which catalyzes the dimerization of purine nucleobases and tryptophan-containing diketopiperazines (TDKPs), yielding C3-nucleobase pyrroloindolines and nucleobase-TDKP dimers. Unlike typical TDKP P450 enzymes reliant on NAD(P)H cofactors and electron transfer systems, PtmB, and its analogs exhibit remarkable peroxidase activity in synthesizing adenine and other modified 6-aminopurine nucleobase-TDKP dimers. Structural analysis of the PtmB-substrate complex, mutation assays, and computational investigations reveal adenine's dual role as both substrate and acid-base catalyst in activating H2O2 to generate Compound I (Cpd I). This initiates a specific radical cascade reaction, facilitating the formation of precise C─C and C─N bonds. Biochemical assays and molecular dynamics simulations demonstrate that adenine's 6-NH2 hydrogen-bonding networks induce necessary conformational changes for H2O2 activation, thereby driving peroxidase activity. This study unveils an unusual catalytic mechanism for the P450 peroxidase system and underscores the pivotal role of nucleobases in enzyme-mediated reactions, which offers different prospects for developing P450 peroxidases and nucleobase-based biocatalysts.

Pyridine‐Boryl Radical‐Catalyzed [3 + 2] Cycloadditions of Alkyne‐Tethered Cyclopropyl Ketones

AbstractBicyclo[3.3.0]octanes represent crucial structural motifs found in various bioactive natural compounds. In this study, we present the first metal‐free formal [3 + 2] cycloadditions of alkyne‐tethered cyclopropyl ketones via pyridine‐boryl radical catalysis, affording bicyclo[3.3.0]octanes with high efficiency and broad substrate scope. This reaction features the generation of ketyl radical by pyridine‐boryl radical and a consecutive 5‐exo‐dig and 5‐exo‐trig radical cascade process.

Dication Disulfuranes as Photoactivatable Sources of Radical Organocatalysts.

The recent development of photoredox and energy transfer catalysis has led to a significant expansion of visible light-driven chemical transformations. These methods have demonstrated exceptional efficiency in converting a wide range of substrates into radical intermediates and generating open-shell catalytic species. However, the simplification of catalytic systems and the direct generation of highly reactive radical organocatalysts through direct visible light irradiation from stable precatalysts remains largely an unrealized goal. This challenge is mainly due to the limited availability of precatalysts that are responsive to visible light. Herein, we introduce a new class of bench-stable dicationic disulfuranes, which release highly reactive thiyl radicals upon blue light excitation. Spectroscopic and computational studies reveal that this reactivity arises from a combination of structural features and intermolecular interactions. This family of molecules has been employed to catalyze radical cascades previously incompatible with photoredox conditions, enabling the efficient formation of 1,2-dioxolanes and 1,3-hydroxyketones in excellent yields and short reaction times.

Dication Disulfuranes as Photoactivatable Sources of Radical Organocatalysts

The recent development of photoredox and energy transfer catalysis has led to a significant expansion of visible light‐driven chemical transformations. These methods have demonstrated exceptional efficiency in converting a wide range of substrates into radical intermediates and generating open‐shell catalytic species. However, the simplification of catalytic systems and the direct generation of highly reactive radical organocatalysts through direct visible light irradiation from stable precatalysts remains largely an unrealized goal. This challenge is mainly due to the limited availability of precatalysts that are responsive to visible light. Herein, we introduce a new class of bench‐stable dicationic disulfuranes, which release highly reactive thiyl radicals upon blue light excitation. Spectroscopic and computational studies reveal that this reactivity arises from a combination of structural features and intermolecular interactions. This family of molecules has been employed to catalyze radical cascades previously incompatible with photoredox conditions, enabling the efficient formation of 1,2‐dioxolanes and 1,3‐hydroxyketones in excellent yields and short reaction times.

Recent Advances in Radical Reactions of 1,n‐Enynes with Phosphorus‐Centered Radicals

AbstractOrganophosphorus compounds have been widely used as achiral and chiral ligands in organic synthesis (PPh3, BINAP, dppe, Duphos, Xantphos, PPFA, Chiraphos, SEGPHOS), flame retardants, functional materials (LED, PV), as well as agrochemicals and medicines due to their broad biological activities. As the privileged versatile building blocks, 1,n‐enynes have been successfully applied in the synthesis of various functionalized cyclic compounds based on their two active unsaturated chemical bonds (C═C double and C≡C triple bonds). With the development of highly selective and efficient methods in organic chemistry, various organophosphorus cyclic compounds synthesis through radical cascade strategy has attracted considerable attention in recent years. In here, we have summarized the recent main achievements in the radical cascade reactions of 1,n‐enynes with phosphorus‐centered radicals. Furthermore, we also displayed the detailed reaction mechanisms in this review.

Photo‐catalyzed Stereospecific Synthesis of Trisubstituted Alkenes Incorporating 3,3‐Difluoro‐γ‐Lactams from Morita‐Baylis‐Hillman Acetates and N‐Allylbromodifluoroacetamides

A photocatalytic methodology has been devised for the stereoselective construction of trisubstituted alkenes incorporating 3,3‐difluoro‐γ‐lactams in 17‐93% yields via a radical cascade process utilizing MBH acetates and N‐allylbromodifluoroacetamides as starting materials. The reaction mechanism involves single‐electron transfer, 5‐exo‐trig cyclization, radical addition, and elimination in a cascade fashion.

Diastereoselective Access to Ester-Substituted cis-Phenanthridinones via Hydrogen Atom Transfer-Involved 1,7-Enyne Bicyclization.

An organophotoredox-catalyzed 1,7-enyne bicyclization for the cis-diastereoselective synthesis of ester-substituted phenanthridinones has been achieved through radical cascade cyclization involving 1,6-hydrogen atom transfer. This transition-metal- and oxidant-free one-pot protocol generates three distinct C-C bonds and two quaternary carbon centers.

Divergent Synthesis of Benzo[4,5]imidazo[2,1-b][1,3]thiazines and α-Trifluoromethyl-β-arylthio Tertiary Alcohols from 2-Mercaptobenzimidazoles and α-CF3 Alkenes.

An efficient and metal-free approach for the divergent synthesis of 2-fluoro-3-aryl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazines and α-trifluoromethyl-β-arylthio tertiary alcohols from 2-mercaptoimidazoles and α-CF3 alkenes has been developed. The chemoselectivity was well controlled by base or light; a series of 2-fluoro-3-aryl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazines were afforded via base-mediated sequential SN2'- and SNV-type reactions. Meanwhile, α-trifluoromethyl-β-arylthio tertiary alcohols could be selectively achieved through visible-light-driven and electron donor-acceptor (EDA) complex-initiated radical cascade thiolation/hydroxylation in the absence of base, transition metal, and external photocatalyst.

Pentafluorosulfanylation of Acrylamides: The Synthesis of SF5-Containing Isoquinolinediones with SF5Cl.

We disclose herein an efficient and facile method for the synthesis of SF5-containing isoquinolinediones with an all-carbon quaternary stereocenter via intramolecular pentafluorosulfanylation of acrylamides using SF5Cl as a pentafluorosulfanylation reagent. The protocol proceeds under mild reaction conditions and enjoys a broad substrate scope, wide functional group compatibility, and high atom- and step-economy. A radical mechanism involving the SF5 radical cascade addition/cyclization of acrylamides is proposed.

Sulfonyl Radical-Induced Regioselective Cyclization of Enamide-Olefin To Form Sulfonylated 6-7-Membered Cyclic Enamines.

Remarkable progress has been made in the radical cascade cyclization of heteroaryl- or aryl-tethered alkenes to construct benzene-fused frameworks via the cracking of aryl C-H bonds. In contrast, the radical cascade cyclization of linear dienes through the cracking of vinyl C-H bonds to construct nonbenzene-fused ring frameworks with endocyclic double bonds has significantly lagged behind, and major advances have largely been restricted to the generation of 5-membered heterocycles, such as pyrrolinones. Herein, we report the silver-mediated regioselective sulfonylation-cyclization of linear dienes with sodium sulfinates to form sulfonylated 6- and 7-membered cyclic enamines.

Modular Synthesis of gem-Difluorotetrahydrocarbazolone Scaffolds via Copper-Catalyzed Cascade Reaction of Bromodifluoroacetyl Indoles and Olefins.

A novel and efficient modular synthesis of gem-difluorotetrahydrocarbazolone scaffolds via copper-catalyzed radical cascade cyclization of bromodifluoroacetyl indoles and olefins has been reported. This operationally simple protocol provides straightforward and practical access to a series of privileged gem-difluorotetrahydrocarbazolone scaffolds from readily available starting materials, with the feature of broad functional group tolerance and mild reaction conditions. Moreover, the method could be used for the late-stage functionalization of bioactive molecules, which opens up the possibility for practical applications.

Photocatalytic Cascade Trifluoromethylation/Cyclization : Selective Synthesis of Trifluoroethylated Benzopyran and Benzopyranone Derivatives

We have realized the photocatalytic radical cascade cyclization reaction, enabling the one‐step synthesis of rare trifluoroethyl benzopyran derivatives with a wide variety of structures and excellent yields. Furthermore, the approach exhibits low catalyst load, strong regional control and wide applicability under mild conditions. The selectivity of this transformation is influenced by the length of the carbon chain of the benzaldehyde, as demonstrated by the density functional theory calculations. Additionally, scaling up the photocatalytic process can be easily accomplished.

Visible Light-Induced Radical Cascade Functionalization of Quinoxalin-2(1H)-ones: Three-Component 1,2-Di(hetero)arylation Approach with Styrenes and Thianthrenium Salts.

The additive-free visible light-induced three-component 1,2-di(hetero)arylation of styrenes was developed using quinoxalin-2(1H)-ones and thianthrenium salts. The purple visible light excitable quinoxalin-2(1H)-ones were utilized for the single-electron transfer to aryl thianthrenium salts, where the generated aryl radical species underwent the addition cascade to styrenes and quinoxalin-2(1H)-ones. The direct aryl radical addition to quinoxalin-2(1H)-ones also led to the formation of a side product, C3-aryl quinoxalin-2(1H)-ones, capable of a photoredox process to help the formation of 1,2-di(hetero)arylation products.

Visible-Light-Mediated Photoredox Radical Cyclization Reaction with Alkyl Boronic Acids Using Molecular Oxygen as a Sole Oxidant

AbstractIndolo[2,1-b]quinazolin-12(6H)-one derivatives are prevalent in many synthetic intermediates, pharmaceuticals, and organic materials. Herein, we developed a photoredox radical cascade cyclization reaction that uses visible light as the primary energy input to promote the reaction, leading to a series of indolo[2,1-b]quinazolin-12(6H)-one derivatives under oxygen conditions.

Mn-Catalyzed Electrooxidative Radical Cascade Cyclization for the Synthesis of 6-Phosphorylated Quinoxalino[2,1-b]quinazolin-12-ones.

Due to their important potential medicinal value, chemists are pursuing mild and efficient methods to synthesize structurally diverse quinazolinone derivatives. In this paper, a series of isocyano-tethered N-aryl quinazolinones were designed and synthesized to conduct electrocatalytic radical cascade cyclization reactions with phosphine oxides by utilizing inexpensive MnII salt as the catalyst. The desired 6-phosphorylated quinoxalino[2,1-b]quinazolin-12-ones were obtained in moderate to good yields.

Alcohols as Alkyl Electrophiles for Deoxygenative Heck Reaction Enabled by Excited State Pd Catalysis.

Here, we present a general method for the photoinduced Pd-catalyzed deoxygenative Heck reaction of vinyl arenes with ortho-iodophenyl-thionocarbonate derived from alcohols. Mechanistic studies reveal that the deoxygenation involves a 5-endo-trig cyclization and fragmentation process, with radical addition identified as the rate-determining step in this transformation. This one-pot procedure demonstrates excellent selectivity for less hindered hydroxyl groups in diols, facilitating late-stage functionalization of complex molecules and scalability to gram-scale synthesis. The protocol highlights significant synthetic potential and can be extended to the cascade 1,1-difunctionalization of isocyanides and the intermolecular radical cascade cyclization of N-arylacrylamides.